"Catch-and-Release" Anti-Carcinoembryonic Antigen Monoclonal Antibody Leads to Greater Plasma and Tumor Exposure in a Mouse Model of Colorectal Cancer.

摘要: In this study, we examined the effects of target expression, neonatal Fc receptor (FcRn) expression in tumors, and pH-dependent binding on disposition monoclonal antibodies (mAbs) murine models colorectal cancer. A panel anti-carcinoembryonic antigen (CEA) mAbs was developed via standard hybridoma technology then evaluated for CEA binding. Binding assessed immunoassay radioligand assays. 10H6, a IgG1 mAb with high affinity at pH = 7.4 (KD 12.6 ± 1.7 nM) reduced 6.0 144.6 21.8 nM), T84.66, which exhibits pH-independent 1.1 0.11 1.4 0.16 nM 6.0), were selected pharmacokinetic investigations. We pharmacokinetics after intravenous administration to control mice bearing tumors (MC38CEA+, LS174T) without (MC38CEA-) or FcRn, doses 0.1, 1, 10 mg/kg. 10H6 displayed linear MC38CEA+ MC38CEA- tumors. T84.66 but dose-dependent nonlinear addition improved plasma profile (i.e., pharmacokinetics, longer terminal half-life), exhibited exposure relative T84.66. lacking FcRn (LS174T), demonstrated rapid clearance low dose. These data are consistent hypothesis that allows dissociation from acidified endosomes, enabling FcRn-mediated protection target-mediated elimination